Search

Background: Brexpiprazole is a dopamine/serotonin receptor partial agonist (D2, 5-HT1A) and antagonist (5-HT2A) approved for treatment of schizophrenia and major depressive disorder (adjunct to antidepressants). Aims: This study aimed to investigate brexpiprazole as monotherapy in acute mania (bipolar I disorder) in two short-term (ST) studies (study 080 and study 081) and one open-label (OL) extension (study 083). Methods: ST studies were three-week randomized, double-blind, flexible dose (2–4 mg/day), placebo-controlled studies. The primary endpoint was mean change in Young Mania Rating Scale (YMRS) total score from baseline to day 21. The OL study was a 26-week flexible dose (2–4 mg/day) study for patients completing the ST studies. Results: A total of 164 and 158 (study 080) and 170 and 162 (study 081) inpatients with DSM-5 mania with/without mixed features were randomized to placebo or brexpiprazole, respectively. The primary analyses did not show a statistically significant difference between brexpiprazole and placebo: study 080: least squares mean difference (95% confidence limits): 0.14 (−1.74, 2.03), p = 0.8797; study 081: −1.62 (−3.56, 0.32), p = 0.1011. OL study patients ( n = 381) demonstrated a gradual improvement in YMRS total score. Akathisia was the only adverse event, with an incidence of ⩾5% with brexpiprazole and more than placebo in the ST studies, or ⩾5% in the OL study. Brexpiprazole was more efficacious in patients with impaired or no insight (predominantly EU patients) than in patients with excellent insight (predominantly US patients). Conclusions: Further studies are necessary to address the potential efficacy of brexpiprazole in acute mania, which should ensure that the study sample is severe enough (especially with regard to insight), and that the dose/titration schedule is not too modest.

Contemporary accounts credit Dr Francis Willis (1718–1807) with facilitating the recovery of King George III from his major episode of acute mania in 1788–9. Subsequently Willis was summoned to Lisbon to advise on the mental health problems of Queen Maria I. This article reports the nature of the illnesses of Maria and her two similarly affected sisters, and uses the program OPCRIT to propose diagnoses of major depressive disorders. The high prevalence of consanguinity and insanity among the Portuguese monarchy and their antecedents probably contributed to their mental health problems. The successive contributions of the Willis family from Thomas Willis (1621–75) to his grand-nephew, Francis Willis (1792–1859), are reviewed; the popular image is somewhat inaccurate and does not highlight their part in the development of psychiatry.

It has been claimed that King James VI/I, an antecedent of King George III, suffered from acute porphyria, and that the disease was passed on to George III through his grand-daughter Sophie, mother of George I. The life of James is reviewed and previously-proposed diagnoses are considered. James’s medical history is discussed in detail and, where possible, examined with validated symptom scales. Using an online database of neurological diseases, the authors show that James’s symptomatology is compatible with a diagnosis of Attenuated (mild) Lesch-Nyhan disease; no evidence was found to support a diagnosis of acute porphyria. In addition, there is evidence of associated Asperger traits which may explain some of the King’s unusual behavioural and psycho-social features.

In this paper we report the application of an extensive database of symptoms, signs, laboratory findings and illnesses, to the diagnosis of an historical figure. The medical diagnosis of Augustus d'Este (1794–1848) – widely held to be the first documented case of multiple sclerosis – is reviewed, using the detailed symptom diary, which he kept over many years, as clinical data. Some of the reported features prompted the competing claim that d'Este suffered from acute porphyria, which in turn was used in support of the hypothesis that his grandfather, King George III, also suffered from the disease. We find that multiple sclerosis is statistically the most likely diagnosis, with neuromyelitis optica a strong alternative possibility. The database did not support a diagnosis of any of the acute porphyrias.

Objectives Two biographies of Admiral Francis Beaufort (1774-1857) have stated that, aged 20-25 years, he suffered from porphyria cutanea tarda (PCT) that was ‘cured’ following severe blood loss during a naval skirmish. We have examined the evidence concerning the nature of his skin disease. Design Primary records, most notably Beaufort's correspondence with his family, his journals and his father's diaries were sought out and analysed. Setting This case report is discussed in the context of 18th-century naval medicine and concepts and treatment of skin disease. Results The description of his lesions, their age of onset, their progression and response to treatment, particularly topical tar and associated features are quite inconsistent with a diagnosis of PCT. His mother, Mary Waller Beaufort (1739-1821), consulted Dr Robert Darwin in 1803 about a painful skin disease affecting her legs. Detailed description of the lesions and a contemporary diagnosis are not available but possible diagnoses include chronic psoriasis and stasis eczema. Conclusions A more tenable diagnosis is that Francis Beaufort had chronic plaque psoriasis remitted by bed rest and convalescence in the sunny Mediterranean climate with cessation of alcohol consumption and improved nutrition as well as topical and oral medications.

This research, based on a study of King George III’s medical records and of contemporary diaries of his courtiers and equerries, further confirms the considerable doubt on the claim of Richard Hunter and Ida Macalpine that the King suffered from recurrent attacks of acute porphyria. The present study examines the above records from a psychiatric viewpoint, together with some additional reports, to re-assess the nature of the King’s maladies. It concludes that he suffered from recurrent mania (four episodes), with chronic mania and possibly a degree of fatuity during the last decade of his life. This is in agreement with previous reports that he suffered from manic-depressive psychosis.

In his otherwise scholarly article on the origins of The Lancet, Professor Jones has in an aside propagated the myth that George III had ‘porphyria-induced madness’.1 Recent detailed review of the 100+ volumes of the King's medical notes together with the correspondence, reports and diaries of courtiers and court officials has confirmed the fallacy of this claim first raised when the British Medical Journal unfortunately published the two articles by Drs Macalpine and Hunter in 1966–1968.2,3 It is most unlikely that The Lancet would have fallen prey to this historical temptation. The relevant papers will appear shortly in the journal History of Psychiatry but a summary of my findings has recently been published in History Today.4 A morning in the British Library reading the relevant Willis manuscript5 would rebut the diagnostic claims of the so-called blue particulate urine (not a feature of any of the porphyrias) and shown that the diagnosis of any of the acute porphyrias cannot be substantiated. Professor Jones is also dismissive of 18th- and 19th-century physicians; they may not have had the MRI, CT and PET scans, and other sophisticated diagnostic procedures available to today's general practitioners at the touch of a pen, but they were certainly keen observers, and in the case of Geo III knew when to call for outside help. The arrival of the Willis family of ‘mad doctors’ was followed by a remission of the King's episodes of acute mania in 1788–1789, 1801 and 1804. In doing so they helped lay the foundations of modern psychiatry, developing the recognition and approaches available today. Some CME of the history of medicine is clearly needed here.